A group of diagnostic Positron Emission Tomography (“PET”) procedures utilize radioactive labeled compounds, wherein the radioactive atoms are positron emitters. Some examples of positron emitting elements include nuclides of carbon, nitrogen, or fluorine. These elements are the backbone of almost all biological active compounds. In order to be able to use these elements, stable isotopes are replaced with a radioactive isotope. The radioactive labeled compounds, called tracers, are transported, accumulated and converted exactly the same way as for non-radioactive compounds. The PET method has possibilities to detect malfunction on a cellular level in the investigated tissues or organs. The method is very sensitive and requires only nanomole quantities of produced radioactive tracers. These radioactive tracers have a half-life in the range from 2 to 110 minutes, (e.g. 11C, t1/2=20.4 min). Karimi et al., Eur. J. Org. Chem., 2005, 2374-2378, Acta Upsaliensis, Uppsala 2002, ISBN 91-554-5452-6 and Rahman et al., Eur. J. Org. Chem., 2004, 2674-2678. Because of the radioactivity, the short half-lives and the submicromolar amounts of the labeled substances, extraordinary synthetic procedures are required for the production of these tracers. The most used precursors for the introduction of 11C in a bioactive molecule are [11C] iodomethane and [11C] methyl triflate used in methylation reactions, [11C]carbon dioxide in the Grignard reaction, and [11C]carbon monoxide in carbonylation reactions. Additionally, an important part of the elaboration of these procedures is the development and handling of new anti-inflammatory [11C]-labeled tracers.
Inflammatory responses are thought to be mediated in part by the prostaglandins (“PGs”) derived from arachidonic acid by the action of prostaglandin H synthase, which is also referred to as cyclooxygenase (“COX”). Khanum et al., Bioorg. Chem., 2004, vol. 32, 211-222.
Recent studies have shown that COX exists in two isoforms COX-1 and COX-2. Both COX are constitutively expressed in most tissues, but COX-2, in contrast COX-1, is the mitogen inducible isoform. The inducing stimuli for COX-2 include pro-inflammatory cytokines and growth factors, implying a role for COX-2 in both inflammation and control of cell growth. COX isoforms are almost identical in structure but have important differences in substrate and inhibitor selectivity and in their intercellular locations. Protective PGs which preserve the integrity of the stomach lining and maintain normal renal function in a compromised kidney, are synthesized by COX-1. In addition to the induction of COX-2 in inflammatory lesions, it is present constitutively in the brain and spinal cord, where it may be involved in the nerve transmission, particularly those for pain and fever. Khanum et al., Bioorg. Chem., 2004, vol. 32, 211-222.
COX is the principal target of nonsteroidal anti-inflammatory drugs (“NSAIDs”) and metabolites of the COX pathway are widely accepted as mediators of the inflammatory response. NSAIDs block the formation of PGs and have anti-inflammatory, analgesic, and antipyretic activity. The discovery of COX-2 has made it possible to design drugs that reduce inflammation without removing the protective PGs in the stomach and kidney made by COX-1. Khanum et al., Bioorg. Chem., 2004, vol. 32, 211-222.
Benzophenone analogues have been identified as potent anti-inflammatory agents. Welstead et al. and Branacaccio et al. have reported the anti-inflammatory activity of benzoylphenylacetic acid. Khanum et al., Bioorg. Chem., 2004, vol. 32, 211-222.
In addition, Vigorita et al. have identified polyaromatic trifluoroacetamides as anti-inflammatory agents. Vigorita et al., Farmaco, 1989, vol. 46, 1074-1079. Accordingly, Khanum et al. synthesized hydroxybenzophenones, aroyl aryloxyacetic acid and acetamide analogues, and evaluated them for their anti-inflammatory activity and side effects. Khanum et al., Bioorg. Chem., 2004, vol. 32, 211-222. Additionally, Unlu et al. synthesized a series of alkanoic acid derivatives and evaluated their analgesic and anti-inflammatory activities. Khanum et al., Bioorg. Chem., 2004, vol. 32, 211-222.
Based on the aforementioned, there is a need to find better radioactive yields, trapping efficiency, and shorter reaction times for [11C]-labeled benzophenone/benzoxazole analogues.
Furthermore, there is a need for creating inflammation imaging agents wherein these agents can be visualized by PET.
Discussion or citation of a reference herein shall not be construed as an admission that such reference is prior art to the present invention.